P-gp
body has in place a safety mechanism whereby some molecules are actively pumped back INTO the gut This efflux mechanism is mainly a function of a transporter in the plasma membrane called P-glycoprotein. P-gps are also present in the brain where they perform a similar function, i.e. prevent noxious substances form entering such a vital organ. P-glycoproteins are also present in the brain where they perform a similar function. Optimisation of Compound XR 9576 gave Compound 22a with a flexible linker side chain which confe confers P-gp inhibition (therefore reduces tumour drug resistance). It has been estimated 15 that the surface area of the human gut is 200 m2. Unfortunately, such a large surface area is also available for the absorption of molecules that would potentially be harmful to the organism. Consequently membrane efflux transporters such as Permeability-glycoprotein (P-gp) act as a safety mechanism aimed at preventing toxins and xenobiotics from entering the general circulation by effectively pumping them back into the gut lumen. P-gp, a member of the adenosine triphosphate (ATP)-binding cassette (ABC) superfamily was discovered in 1976 16 and was originally identified as a key reason for multidrug resistance in treatment of certain cancers.17 It is expressed in intestinal epithelia, hepatocytes, kidney proximal tubules, blood-brain barrier (BBB) endothelia, and placental trophoblast. Vinblastin, Verapamil Quinidine and Omeprazole are known P-gp ligands 18, a property which has consequences on their oral absorption. Glibenclamide, a type 2 diabetes drug known to act at the Sulfonyl Urea Receptor (SUR) is itself both a substrate and an inhibitor 19 for P-glycoprotein. Many authors 20 21 22 have suggested that gut wall CYP3A4 and P-glycoprotein act in a concerted manner to control the absorption of their substrates. This is based on the large overlap of substrates between the two and the proximity of their expression within the gut wall. Thus, it is proposed that P-glycoprotein effectively recycles its substrates, allowing CYP3A4 several opportunities to metabolize compounds in the gut. In this way, a small amount of CYP3A4 in the gut wall (relative to the liver content) can exert a profound extraction of the compound. For example, a study 23 of the gastrointestinal absorption of the HIV protease inhibitor, Saquinavir mesylate (Invirase®), whose oral bioavailability is low, variable, and significantly increased by co-administration with Ritonavir was carried out. Both Saquinavir and Ritonavir were found to be P-gp substrates. Active efflux was temperature dependent, saturable and inhibited by Verapamil and Cyclosporin A. Saquinavir and Ritonavir decreased each other's secretory permeability and hence elevated their net transport by the absorptive pathway. Together with sensitivity to gut-wall metabolism by cytochrome P-450 3A, it was proposed that this may partially account for the low and variable oral bioavailability of Saquinavir in clinical studies and for its increased bioavailability after co-administration with Ritonavir. Further it has been shown that P-glycoprotein mRNA levels increase longitudinally along the intestine, with the lowest levels in the stomach and highest in the colon 24, an observation that has implications for controlled release technology. Corinne KAY (n.d.) ‘ADME – When the Path Matters More than the Destination.’, online Available from: http://learn2.open.ac.uk/pluginfile.php/388971/mod_resource/content/1/Kay_2010.pdf (Accessed 12 May 2012).